4-acylamino-1,2,4-triazole derivatives

ABSTRACT

PHARMACEUTICAL ACTIVE 4-ACYLAMINO-1,2,4-TRIAZOLE DERIVATIVES HAVING THE GENERAL FORMULA:   4-(A-B-CO-N(-R1)-)-1,2,4-TRIAZOLE   IN WHICH R1 IS TETRAHYDROFURFURYL OR AN ALKYL HAVING 1-4 CARBON ATOMS, A IS PHENYL, NAPTHYL, BENZYLTHIO OR BENZYLOXY, B IS A SINGLE BOND, TETRAHYDROFURYL-ETHYL OR A STRAIGHT OR BRANCHED ALKYL HAVING 1-5 CARBON ATOMS.

United States Patent 3,711,496 4-ACYLAMlN0-1,2,4-TRIAZOLE DERIVATIVES Max Matter, Basel, and Karl Michel, Wohlen, Switzerland, assignors to Aktiebolaget Bofors, Bofors, Sweden No Drawing. Filed Sept. 23, 1970, Ser. No. 74,921 Claims priority, application Switzerland, Sept. 24, 1969, 14,448/ 69 Int. Cl. C07d 55/06, 99/04 US. Cl. 260--308 R 6 Claims ABSTRACT OF THE DISCLOSURE zyloxy, B is a single bond, tetrahydrofuryl-ethyl or a stralght or branched alkyl having 1-5 carbon atoms.

The present invention relates to novel 4-acylamino- 1,2,4-tr1azole derivatives having the general formula:

N in which R is tetrahydrofurfuryl or an alkyl having 14 carbon atoms, A is phenyl, naphthyl benzylthio or benzyloxy and B is a single bond, tetrahydrofurylethylene or a straight or branched alkylene with 1-5 carbon atoms.

The novel compounds have valuable pharmaceutical properties. In particular they are very active as analgeticsantiphlogistics and therefore they are very suitable for the treatment of diseases which produce information such as rheumatic all'ections and thrombophlebitis.

The invention also relates to a process for the preparation of the novel compounds having the above general Formula I. This process is characterized in that a 4- acylamino-1,2,4-triazole having the general formula:

in which A and B have the above'stated meanings, is alkylated at the nitrogen atom in the side chain by means of a compound that is capable of attacking the R group which has the above stated meanings.

Compounds, which are capable of attacking the R group are diazolalkanes or reactive esters of an alcohol having the general formula R --OH.

As such reactive esters in particular those of strong inorganic or organic acids, e.g. halogen hydracids, sulphuric acid or organic sulphonic acids, such as aryl sulphonic acids, should be mentioned.

When a diazoalkane, such as diazomethane or diazoethane is used as the alkylating agent, the reaction is carried out in an inert solvent such as methanol, ethanol, diethylether or a cyclic ether such as tetrahydrofurane, preferably at lower temperatures (about +30 C.). The reaction with the reactive esters is carried out in the usual manner in the' presence of absence of diluting agents and, if desired, in the presence of basic condening agents, such, as alkali hydroxides, alcoholates, hydrides or amides. When alkylating With an ester of sulphuric acid, such as dimethyl or diethyl sulphate, or with an aryl sulphonic ester, such as p-toluenesulphonic acid-n-propyl ester, -tetrahydrofurfuryl ester or benzenesulphonic acidn-butyl ester the reaction components are preferably reacted with each other in the absence of a solvent at higher temperatures (about 100-200 C.).

The starting materials as used in the process of the invention are novel and they could be prepared by means of per se known methods.

The novel compounds may be used as medicines, e.g., in the form of pharmaceutical preparation, which contain the novel 4-acylamino-1,2,4-triazole derivatives in mixture with a pharmaceutical, organic or inorganic carrier material that is suitable for enteral, parenteral or topical administration. As the carrier material such substances as water, gelatine, milk sugar, starch, magnesium stearate, talc, vegetable oil, fenzyl alcohol, rubber, polyalkylene glycols, Vaseline, cholesterol and other well-known pharmaceutical carrier-s could be used. The pharmaceutical preparations may be in the form of tablets, drages, ointments, creams or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants such as preservatives, stabilizing agents, humectants or emulsifiers, salts [for changing the osmotic pressure or buffers. They may also contain further therapeutical substances, such as local anesthetics. The preparation of such pharmaceutical preparatives is carried out in per se known usual methods.

The invention will be explained in greater detail in the following examples.

EXAMPLE 1 To a solution of 9.1 g. (0.03 mole) of 4-[a-ethYl-abenzylthio-n-butyryl)-amino]-1,2,4-triazol in 150 ml. tetrahydrofur-an a solution of diazomethane in ether was added at O3 C. until the mixture became yellow. The reaction solution was placed in an ice-bath for three hours and was thereafter evaporated in a water bath, and finally in vacuo. The oily residue was dissolved in chloroform-hexane (1:4) and was filtered through ten times its weight of aluminium oxide (Woelm neutralAkt. I). The filtrate was evaporated once again and the residue was recrystallized from 60 ml. benzene-hexane (1:2). 5.45 g. (57%) 4 [N-(a-ethyl u-benzylthio-n-butyD- methylamino1-1,2,4-triazol having a melting point of 9 C. were obtained. After one recrystallisation from acetic ester-hexane (1:2) the melting point rose to 99- 100 C.

The starting material 4-[(a-ethyl-a-benzylthio-n-butyryl)-amin0]-1,2,4-triazole can be prepared in the following way: To a solution of 2.3 g. (0.1 mole) of sodium in 70 ml. of absolute methanol 25.2 g. (0.1 mol) of a-ethylot-benzylthio-n-butyric acid-methylester and 8.4 g. (0.1 mol) of 4-amino-1,2,4-triazol were added and the mixture was refluxed for 24 hours. The reaction mixture was evaponated in vacuo, the residue was dissolved in 30 ml. of water and the aqueous solution was acidified (congo red) with 2 N hydrochloric acid. After standing in the cold a colorless crystalline precipitate was obtained, filtered by suction, washed with ice-water and recrystallized from 100 ml. of methanol after being dried in a desiccator. The yield of the product was 15.4 g. (51%) and the melting point was 1534 C.

EXAMPLE 2 A mixture of 6.0 g. (0.03 mol) of 4-(phenylacetylamino)-1,2,4-triazol and 7.7 g. (0.03 mol) of tetrahydrofurfuryl-p-toluene-sulphonate was held for 2 hours in an oil bath of C. After cooling the melt was dissolved in 90 ml. of water and 15 ml. of 2 N sodium hydroxide and the solution was extracted 3 times with 10 ml. portions of chloroform. After drying with sodium sulphate the combined chloroform layers were evaporated, the residue was redissolved in chloroform-hexane (1:1) and was filtered through 50 g. of aluminum oxide (Woelm Melting Example point, No. Product C.

3 4-(Nflit-napthylacetyl-tetrahydrofurfuryl- 118-20 amin)-1,2,4-triazole. 4 4-(N-phenylacetyl-n-propyl-amino)4,2,4- 140-1 triazole. 5 4-(N-phenylaeetyl-n-butyl-amino)-l,2,4-triazole 148-9 EXAMPLE 6 A mixture of 4.9 g. (0.02 mol) of 4-[N-(u-phenyl-isovaleryDamino] -'1,2,4-triazole and 2.1 m1. (0.022 mol) of dimethylsulphate was heated 2.5 hours at 160 C. The clear melt was dissolved in 40 m1. of water and 13 ml. of sodium hydroxide solution and the solution was extracted three times with 50 m1. portions of chloroform. The chloroform layers were washed with 50 m1. of water, dried with sodium sulphate and evaporated in vacuo. After recrystallisation of the residue from 50 ml. of ether 3.8 g. (74%) of 4- [N-(a-phenyl-isovaileryl) -methylamimo]-1,2,4tniazole having a melting point of 126-7 C. were obtained. After a further recrystallisation from acetic ester-hexane (1 :3) the melting point rose to 1289 C.

The starting material can be prepared according to the procedure of Example 1 by refluxing-for 15 hours a solution of 1.82 g. (0.079 mol) of sodium and 15.2 g. (0.079 mol) of a-phenyl-isovaleric acid methylester and 6.64 g. (0.79 mol) of 4-am"no-1,2,4-triazole. After the usual treatment and recrystallization of the raw product from 120 ml. of chloroform-ether (1:3) 15.9 g. (82%) of pure 4- [N- (a-phenyl-isova'leryl) amino] -1,2,4-tr iazole having a melting point of 1434 C. were obtained. The compounds listed in the following table were prepared according to the method described in Example 6.

In the following table the starting materials for the Examples 3-5 and 7-17 are listed. These compounds can be prepared according to methods described in the Examples 1, 2 and 6.

Starting material in Melting Example point, No. Product 3, 15 4-(a-naphtylaeetyl-amino)-1,2,4-triazole 220-1 4, 5, 14 4-(phenylaeetyl-amino)-1,2,4-triazole 202-3 7 4-[N-(a-phenyl-n-butyryl)-amino]-1,2,4=-triazole 136-7 8 4-[tN-(cl-PhBIlYl-iSOblltYl'Yl)-3JI]iIl0]-l,2,4- 177-8 rrazo e; 9 4-[N-(a-phenyl-n-eaproyl)-arnino]-1,2,4-triazole..- -8 10 4-[N-(B-phenyl-isovaleryl)-arnino]-1,2,4-triazole.- 134-5 11 4-[N-('y-phenyl-n-butyry1)-amino]-1,2,4-triazole 135-6 12 4-{N-[a-phenyl-B-tetrahydrefuryl-(Z)- 161-2 propienyH-amino}-1,2,4-triazole. 13 4-(benzoyl-amino)-1,2,4-triazole 241-3 16 4-[N-(a-beuzyloxy-isobutyryl)-am.ino]-1,2,4- 179-80 triazole. 17 4-[N-(a-ethyl-a-benzyloxy-n-butyryl)-amino]- 127-9 1,2,4-triazo1e.

We claim: 1. A compound of the formula NN-C 0-3 A wherein R is selected from the group consisting of tetrahydrofurfuryl and an alkyl having from 1-4 carbon atoms, B is an alkylene having from 1-5 carbon atoms, which alkylene may be branched or straight, and A is selected from the group consisting of phenyl, naphthyl, benzyloxy and benzylthio. 2. A compound according to claim 1 wherein R is methyl.

3. A compound according to claim 2 wherein and A is benzylthio.

4. A compound according to claim 2 wherein B is the group and A is benzyloxy. 5. A compound according to claim 2 wherein B is the group --(BCH3 and A is benzyloxy. 6. A compound of the formula N CH3 References Cited Chemical Abstracts, Sixth Collective Index, vols. 51- 55, 1957-196 1, subjects SP-Z, pp. 1l'938s-1'1939s.

Wagner et al., Synthetic Organic Chemistry, (New York, 1953), p. 572.

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R. 424-269 

